The beta cell response to glucose, evaluated at two hyperglycemia plateaus (plus 40 and plus 125 mg/dl above basal), was similar in old, middle, and young subjects. The amount of glucose metabolized per unit of insulin secreted was significantly reduced in the old subjects, indicating the presence of tissue insensitivity to insulin. Tissue sensitivity to insulin at euglycemic levels (insulin clamp technique) was also significantly reduced in the older subjects. The decrease in tissue sensitivity to insulin could not be explained by impaired suppression of hepatic glucose production which was similar in young and old subjects. These results indicate that the primary cause of the decrease in glucose metabolism with age is diminished tissue sensitivity to insulin. Since suppression of hepatic glucose production is similar in young and old subjects, the primary site of insulin resistance appears to reside in peripheral tissues (muscle and adipose). The beta cell response to glucose is not affected by advancing age.